At least some 2-alkoxy-estra-3,17.beta.-diols (hereinafter "2-alkoxy estradiols") have anticancer activity. For example, when tested in mice, 2-methoxy estradiol (1) acts as a potent inhibitor of neovascularization of solid tumors and inhibits their growth at doses which produce no apparent signs of toxicity (Fotsis et al., Nature 368:237 (1994)). Other 2-alkoxy estradiols that are believed to have anti-cancer activity are disclosed in co-pending U.S. provisional patent application "Novel 2-Alkoxy Estradiols and Derivatives Thereof", filed on Mar. 13, 1997 (Attorney Docket No. PEL95-15p). 2-Methoxy estradiol (1) is thought to inhibit tumor growth act by: 1) inhibiting DNA synthesis and mitosis (Breuer et al., Naturwissenschaft 12:280 (1960) and Gelbke et al., J. Steroid Piochem, 7:457 (1976)); 2) inhibiting tubulin polymerization or causing the formation of tubulin polymer with altered morphology and stability properties (D'Amato et al., Proc. Natl. Acad. Sci. U.S.A. ##STR3## 91:3964 (1994)); or 3) inhibiting angiogenesis, i.e. the creation of new blood vessels required for the growth of solid tumors (Fotsis et al., Nature 368:237 (1994), Folkman et al., Nature 339:58 (1994) and Blood et al., Biochim. Biophys. Acts et al., 1032:89 (1990)).
Syntheses previously employed to prepare 2-alkoxy estradiols have often suffered from low yields and a need to utilize tedious purification techniques. For example, one reported synthesis of 2-methoxy estradiol (1) involves the preparation of 2-formyl-.beta.-estradiol dibenzyl ether (2) ##STR4## as a key intermediate by formylation of .beta.-estradiol (3), followed by benzylation of the two hydroxyl groups (Cushman et al., J. Med. Chem. 38:2041 (1995)). However, yields less than 10% are typically obtained from the two reactions. In addition, because the formylation reaction gives a mixture of regioisomers, 2-formyl-.beta.-estradiol dibenzyl ether (2) must be purified by chromatography, which is generally considered to be an inefficient method of purification for large scale syntheses.
Therefore, a need exists for a method of synthesizing 2-alkoxy estradiols that overcomes or minimizes the above-mentioned problems.